Propranolol hydrochloride-containing non-pareil seeds (sugar spheres) require a coating of water insoluble ethylcellulose of less than 2% by weight to mimic the drug release profile of INDERAL® LA when applied from a 98/02 acetone/purified water solution. Due to extremely low spray time, a significant batch to batch variability in drug release profile can occur. There was thus a desire to minimize batch to batch variability in drug release profile. Batch to batch variability may be improved by incorporating a water soluble film forming agent in the ethylcellulose membrane such that a significantly higher coating level, less susceptible to batch to batch variation, would be desired to provide a drug release profile mimicking that of INDERAL® LA.
U.S. Pat. No. 4,138,475 to McAinsh et al. discloses controlled release oral formulation comprising coated spheroids of propranolol or a pharmaceutically acceptable salt thereof, each spheroid coated with a mixture of 80 to 100% by weight of ethylcellulose, preferably having a viscosity of 50 cps at 20° C., 20 to 0% by weight of hydroxypropyl methylcellulose and optionally up to 20% plasticizer based on the total weight of the membrane. These spheroids prior to membrane coating comprise 40 to 65% by weight propranolol or a pharmaceutically acceptable salt thereof and 35 to 60% by weight of microcrystalline cellulose and are prepared by extrusion and spheronization. The ratio of ethylcellulose to hydroxypropylcellulose and coating thickness depend upon the desired controlled release characteristics.
U.S. Pat. No. 4,587,118 issued to Hsiao discloses a controlled release theophylline oral formulation comprising coated micropellets; each pellet is designed to release theophylline at an approximately constant rate. The pellet comprises a drug containing core, which is then coated with a mixture of about 90-70% by weight of ethylcellulose and about 10-30% by weight of hydroxypropyl cellulose. The ratio of ethylcellulose to hydroxypropylcellulose and coating thickness depend upon the desired control release characteristics.
U.S. Pat. No. 4,752,470 issued to Mehta teaches the art of making a controlled release indomethacin formulation comprising coated pellets of indomethacin; each pellet is designed to release indomethacin in both immediate and sustained release form. The pellet comprises a drug-containing core, which is then coated with a mixture of plasticized ethylcellulose and hydroxypropyl cellulose or hydroxypropyl methylcellulose. The loaded pellets are preferably composed of 5-30% by weight of indomethacin and coated with 0.5-10% by weight of ethylcellulose and hydroxypropylcellulose or hydroxypropyl methylcellulose, the ratio of ethylcellulose to hydroxypropylcellulose/hydroxypropyl methylcellulose depending upon the desired control release characteristics.
U.S. Pat. No. 4,957,745 issued to Jonsson et al. describes the art of making a controlled release formulation of a salt of metoprolol comprising a multitude of metoprolol cores prepared by layering the drug onto inert silicon dioxide beads, wherein the core is coated with a metoprolol permeable membrane of essentially ethylcellulose or a mixture of hydroxypropyl methylcellulose and ethylcellulose, the ratio of ethylcellulose to hydroxypropyl methylcellulose depending upon the desired control release characteristics.
U.S. Pat. No. 5,133,974 issued to Paradissis et al. discloses a controlled release formulation comprising a mixture of approximately 0-50% immediate release particles containing a drug, an inert substrate, a binder coated with talc, and up to 100% of extended release particles comprising the immediate release particles coated with a dissolution modifying system containing plasticizers and a film forming agent. Optionally, a drug is included in the coating. Film forming agents include ethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose and mixtures thereof.
U.S. Pat. No. 5,472,708 issued to Chen discloses the art of making a tablet which rapidly disintegrates in the aqueous environment of use, comprising a plurality of pellets embedded in the tablet comprising drug containing cores and a swelling agent having a dissolution rate controlling polymer membrane of a mixture of water-insoluble ethylcellulose and a water soluble film forming polymer, and a permeability reducing agent. The water-soluble polymer is selected from a group containing cellulose acetate phthalate, hydroxypropyl methylcellulose, and polyvinylpyrrolidone, the polymer exhibiting greater solubility at alkaline pH's being preferred. The swelling agent has the property of increasing in volume on exposure to the aqueous environment of use, thus causing rapid release of the drug following bursting of the bead.
Propranolol [1-(isopropyl amino)-3-(1-naphthyloxy)-2-propanoyl] is a beta-adrenergic blocking agent and as such is a competitive inhibitor of the effects of catecholamines at beta-adrenergic receptor sites. The principal effect of propranolol is to reduce cardiac activity by diminishing or preventing beta-adrenergic stimulation. By reducing the rate and force of contraction of the heart, and decreasing the rate of conduction of impulses through the conducting system, the response of the heart to stress and exercise is reduced. These properties are used in the treatment of angina in an effort to reduce the oxygen consumption and increase the exercise tolerance of the heart. Propranolol is also used in the treatment of cardiac arrhythmias to block adrenergic stimulation of cardiac pacemaker potentials. Propranolol is also beneficial in the long-term treatment of hypertension. Other uses of propranolol are in the treatment of migraine and anxiety.
Propranolol is normally administered as propranolol hydrochloride tablets or as long acting INDERAL® LA.